1-allyl ergot alkaloid derivatives, methods for producing the same and the use thereof for preventing and treating migraine

ABSTRACT

This invention relates to 1-allyl ergot alkaloids and their derivatives with selective antagonistic properties to 5-HT 2  receptors for the prevention of, and relief from, migraine-related headache, Parkinson&#39;s disease, disorders of the thrombocyte function, etc.

This invention relates to a novel class of ergot alkaloid derivativeswith selective antagonistic properties to 5-HT₂ receptors for theprevention of, and relief from, migraine-related headache, Parkinson'sdisease, disorders of the thrombocyte function, etc.

BACKGROUND AND STATE OF THE ART

Migraine is one of the most common diseases. About 10% of the populationsuffer from it (Worthington, 1996, Current migraine theory, Can. J.Clin. Pharm., 3, 39-51). This makes it one of the genuinely endemicdiseases.

The distinguishing characteristic of classical migraine is an earlystage accompanied by impaired vision, the so-called visual aura (K.Kranda, J. J. Kulikowski, 1984, Visual Aura in classical migraine, in:Neurobiology of Pain, eds. Holden & Wilmslow, MUP) that can last justminutes or for several hours. Unilateral or bilateral pulsating pain mayfollow the visual aura. Occurrence of the visual aura is only reportedby about 20% of people suffering from migraine and defines the so-called“classical migraine” (M. L. Leone et al., 1995, A review of thetreatment of primary headaches, Ital. J. Neurol. Sci., 16, pp. 577-586).The visual aura is not always followed by headache, and some patientsmay have pain attacks with or without the visual aura in differentincidents (W. F. Stewart et al., 1992, Prevalence of migraine headachein the United States, J.A.M.A., 267, pp. 64-69); J. Olesen et al., 1994,Migraine classification and diagnosis, Neurol., 44, pp. 56-510).

Summarizing, the classical migraine consists of two main phases: a) theaural phase that may not always occur, and b) the acute, painful phasecharacterized by headache. This latter headache phase is characterizedby throbbing pain and nausea. It is frequently accompanied byphotophobia or sensitivity to noise and can last for days (P. J.Goadsby, 1997, Current concepts of the pathophysiology of migraine,Neurol. Clin., 15, pp. 27-42).

The causes and mechanisms of migraine have not been fully understood.Depression spreading in the cerebral cortex has been proposed as theinitiator of the visual aura of classical migraine (Lauritzen, 1994,Brain, 117, pp. 199-210). However, theoretical considerations of thecytoarchitecture of the visual cortex make this hypothesis seem not verylikely (K. Kranda, J. J. Kulikowski, 1984, Visual Aura in classicalmigraine, in: Neurobiology of Pain, Eds. Holden & Wilmslow, MUP).

Numerous pharmaceuticals have been proposed or are already in use forthe treatment and prevention of migraine. These include analgesics,antihistamines, calcium channel blockers, and the group of serotoninagonists/antagonists such as ergot alkaloids, sumatriptan, pizotifene,and propanolol. Other pharmacological classes can potentially be usedfor migraine treatment and prevention such as vasodilators,neuroleptics, β-receptor blockers, and antiepileptics such as sodiumvalproate.

Although considerable progress has been made in migraine treatment inrecent years such as using sumatriptan, a 5-HT₁ agonist, patients havingthis disease are often misdiagnosed and inappropriately treated(Worthington, 1996, Can. J. Clin. Pharm., 3, pp. 39-51). None of theavailable treatments causes permanent relief from migraine-typeheadache. For example, the disease reoccurs within a period of 24 hoursin 40% of the patients that were given sumatriptan. All substances usedin treatment as yet are not very specific to serotonin receptors, whichcauses side effects (such as coronary constriction).

5-HT_(2B) antagonists are said to have great potential for theprevention and treatment of migraine. It has been observed that5-HT_(2B) agonists such as m-chlorophenyl piperazine, can cause migraineattacks in sensitive individuals (Fozard and Gray, 1989, TrendsPharmacol. Sci, 10(8), pp. 307-309). Inversely, HT2B3 antagonists canprevent a migraine outbreak (Kalkman, 1994, Life Sci., 54, pp. 641-644).

The most effective pharmaceuticals as yet in migraine prevention,methysergide, pizotifene, and propanolol, have an antagonistic effect on5-HT_(2B)-Rezeptoren (Kalkman, 1994, Life Sci., 54(10), pp. 641-644).Methylergometrine as the main active metabolite of methysergide inhumans also has a strong antagonistic effect on 5-HT_(2B) receptors(Fozard and Kalkman, 1994, Arch. Pharmakol. 350(3), pp. 225-229).

5-HT_(2B) receptors were localized in endothelial cells (intima)including the endothelial cells of blood vessels in the brain (Ullmeret. al, 1995, FEBS-Lett., 370(3), pp. 215-221) and trigger vesselrelaxation by releasing nitric oxide (NO). NO may also have a part incausing migraine (Olesen et al., 1994, Ann. Neurol., 28, pp. 791-798).All migraine agents mentioned above have considerable side effects.

Another desired characteristic for an anti-migraine effect is the strongefficacy of the substances described on thrombocytes as variousdisorders of the thrombocyte function are known to occur with migraine.These manifest themselves by increased adhesion and aggregation during afit, in sludging and the resulting microcirculation as well as therelease of serotonin, thromboxane A and other vasoactive substances (seethe overview in S. Diamond, Migraine Prevention and Management, MarcelDekker, Basel, 1990). The effects on thrombocytes are desired wheneverthrombocyte aggregation is disturbed or increased, independent ofmigraine.

It is the problem of this invention to provide a pharmaceutical for theprevention and relief of migraines.

According to the invention, novel allyl ergot alkaloid derivatives ofthe general formula (I) are provided

wherein

-   -   R₁ represents a methyl, ethyl, n-propyl, i-propyl, or allyl        group,    -   R₂ is hydrogen or a NHCON(C₂H₅)₂ group,    -   R₃ is hydrogen or a —OCH₃ group, and    -   R₄ represents a methyl, ethyl, n-propyl, i-propyl, or —CH₂OH        group, a        group in which R₇ represents an unbranched or branched alkyl        group, aryl group, or aralkyl group containing 1-18 carbon        atoms, a carboxy group or a group of the formula (II)        in which R₅ is an unbranched or branched alkyl group containing        1-4 carbon atoms and R₆ is an unbranched or branched alkyl group        containing 1-5 carbon atoms, an aryl, an aralkyl or a        —(CH₂)₂SCH₃ group, and        the bond between C atoms 9 and 10 is either a single or a double        bond while the residue R₃ is omitted.

In a preferred embodiment, R₄ is formed by a group of the formula (II)and R₅ represents a methyl, ethyl, i-propyl, or s-butyl group.

In another preferred embodiment, R₄ is a group of the formula (II) andR₆ represents an ethyl, i-propyl, i-butyl, s-butyl, i-pentyl, or benzylgroup.

Most preferred are 1-allyl terguride, 1-allyl festuclavine, and 1-allyldihydroergotamine.

The compounds according to the invention of the general formula (I) areproduced by reacting a compound of the general formula (III)

wherein

-   -   R₁ represents a methyl, ethyl, n-propyl, i-propyl, or allyl        group,    -   R₂ is hydrogen or a NHCON(C₂H₅)₂ group,    -   R₃ is hydrogen or a —OCH₃ group, and    -   R₄ represents a methyl, ethyl, n-propyl, i-propyl, or —CH₂OH        group, a        group in which R₇ represents an unbranched or branched alkyl        group, aryl group, or aralkyl group containing 1-18 carbon        atoms, a carboxy group or a group of the formula (II)        in which R₅ is an unbranched or branched alkyl group containing        1-4 carbon atoms and R₆ is an unbranched or branched alkyl group        containing 1-5 carbon atoms, an aryl, an aralkyl or a        —(CH₂)₂SCH₃ group, and        the bond between C atoms 9 and 10 is either a single or a double        bond while the residue R₃ is omitted, with allyl bromide in        CH₂Cl₂, optionally adding tetraethyl ammonium hydroxide and        NaOH.

The allyl ergot alkaloid derivatives of the general formula (I) of theinvention may optionally be converted into an acid addition salt usingthe common procedures, preferably the sulphate, bisulphate, nitrate,phosphate, hydrogen phosphate, hydrochloride, hydrobromide, hydroiodide,acetate, tartrate, lactate, citrate, gluconate, fumarate, maleate,hydroxyl maleate, succinate, pamoate, benzoate, propionate, pyruvate,oxalate, malonate, cinnamate, salicylate, alkyl sulphonate, arylsulphonate, and aralkyl sulphonate.

Another object of the invention are pharmaceuticals containing one orseveral allyl ergot alkaloids of the general formula (I). Thesealkaloids have selective antagonistic properties to 5-HT_(2A) and5-HT_(2B) receptors.

Due to the allyl group inserted at N¹, the compounds of the inventionshow surprising stability against metabolic decomposition, which extendsthe time the pharmaceutical is effective. In addition, selectiveefficacy on 5-HT_(2B) or 5-HT_(2A) receptors is higher than for otherknown compounds after introducing the allyl group. Increased specificityremains for 1-allyl ergotamine and 1-allyl dihydroergotamine even whenlosing the partially agonistic component of the parent substances.

Selective antagonistic properties to 5-HT_(2A) and 5-HT_(2B) receptorsmakes the compounds according to the invention highly suitable as apharmaceutical for the prevention and treatment of migraine. One or theother property in specific expression is particularly suited for actingduring an acute fit in which serotoninergic nucleus raphe dorsalis isactivated to an increased extent according to H. Raskin and O.Appenzeller, or in fit prevention where serotonin receptors on vesselsplay a specific part.

In addition, these substances have an inhibitive effect on thrombocyteaggregation. In addition to treating migraine and accompanying disordersof the thrombocyte function, the substances according to the inventionare also suitable for treating disturbed or increased thrombocyteaggregation independent of migraine.

The substances according to the invention also show a high affinity tovarious dopamine receptors, first of all, to the D₂ receptor. This makesthem suitable for treating Parkinson's disease and other dopaminedeficiency conditions such as Restless Legs Syndrome andhyperprolactinemia. Furthermore, the substances according to theinvention are suitable for use as antipsychotics due to their partiallyagonistic and partially antagonistic effects.

Likewise, the allyl ergot alkaloid derivatives of the general formula(I) are suited for the prevention and/or treatment of mental diseasesand general diseases of the nervous system.

An object of this invention are pharmaceuticals for oral, sublingual,transdermal, rectal, topical, and parenteral (such as intravenous)application that, in addition to the common substrates and adjuvants,contain a compound of the general formula (I) or its pharmaceuticallycompatible acid addition salt.

The pharmaceutical according to the invention can be administered in aspecial depot form facilitating controlled release of the activeingredient, continuous release such as a transdermal pad, intermittent,delayed, or double release.

Dosage of the pharmaceutical according to the invention depends on thepatient to be treated, the severity of the symptoms and the form ofadministration. The effective dose for die oral, sublingual,transdermal, rectal, topical, and parenteral administration preferablyis 0.001-20 mg per kg of body weight and day. The pharmaceuticalsaccording to the invention are produced in a known way using the solidor liquid substrates and adjuvants common in pharmaceutical engineeringdepending on the form of application.

Substrates and adjuvants may include binding agents, fillers, tablettingaids, diluents, solubility promoters, dyes, flavoring substances,wetting agents, emulgators, pH buffer additions, suspension aids,non-aqueous adjuvants and preservatives.

A filler may be selected from cellulose, mannitol, and lactose.Potential solubility promoters are starch, starch derivatives, andpolyvinyl pyrrolidone. Adding EDTA to a solution of the activeingredient is beneficial. Sodium lauryl sulphate, lecithin, sorbitanmonooleate, and gum arabic may be selected as emulgators. A suspensionaid may be selected from sorbitol, methyl cellulose, gelatin,hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate geland hydrated nutrient fats. Potential non-aqueous adjuvants are almondoil, coconut oil, glycerin ester, propylene glycol, and ethyl alcohol.Suitable preservatives are methyl-p-hydroxybenzoate,ethyl-p-hydroxybenzoate, sodium acid sulfite, and ascorbic acid.Magnesium stearate may be used as a lubricant.

The active ingredient can be applied orally in solid form as tablets,capsules, agglomerations, powders, and lozenges or in liquid form asaqueous solution, suspension, syrup, or soluble powder. Anotherpotential form of application would be an oral spray.

Options for parenteral application are by subcutaneous, intramuscular,or intravenous injection. The active ingredient of the general formula(I) can be a liquid suspension or a solution or can be dissolved orsuspended shortly prior to injection. Addition of emulgators or wettingagents to a suspension can cause even distribution of the activeingredient in the liquid. Potential liquid substrates are salinesolutions or glycerin. The preferred concentration of the activeingredient is 0.1 to 10%.

For transdermal application, the active ingredient of the generalformula (I) is distributed in a carrier matrix that may be selected frommineral oil, paraffin oil, a polyacrylate, or a wax. A transdermaltransport enhancer and/or structure breaker such as dimethyl sulfoxideor propylene glycol may be added.

EXAMPLES

The examples below are given to illustrate the invention withoutlimiting it.

Example 1 Synthesis and Characterization of Compounds According to theInvention of the Formula (I)

A solution of (5R,8S,10R) terguride (4 g,11.7 mM) in CH₂Cl₂ (160 ml) wasmixed with a 20% (v/v) solution tetraethyl ammonium hydroxide (8 ml) in24 ml 50% (w/v) NaOH. Then allyl bromide (5 ml, 58.6 mM) is added bydropping under constant stirring. Stirring is kept up for 5 minutesafter adding the allyl bromide. After separating the organic phase, theproduct is washed twice with water and evaporated in a vacuum. Theresidue was chromatographed above a silica gel column (40 g) using asCH₂Cl₂ eluent. The fractions with allyl terguride were dried, and thepure product was crystallized from a diethyl ether/petrol ethersolution. The yield was 2.5 g of 1-allyl-(5R,8S,10R)-terguride.

All other compounds of the general formula (I) were synthesized using asimilar procedure.

The structure was elucidated using mass spectroscopy and ¹H and ¹³C-NMR.The mass spectra were taken using a Finnigan MAT 90 (double-focusing, BEgeometry) under the following conditions:

-   -   Ionization energy: 70 eV    -   Temperature of the ion source: 250° C.    -   Cathode emission current: 1 mA    -   Accelerating voltage: 5 kV; DIP: 170° C.

¹H and ¹³C-NMR spectra:

-   -   Frequency: 400 or 100 MHz, respectively    -   Solvent: CDCl₃, 25° C.    -   Varian Inova 400 spectrometer    -   TMS standard

Results of the characterization:

A) Melting points of selective compounds according to the invention (°C.) (for trivial names and the structure of residues R₁-R₆: see Table1): 1-Allyl festuclavine 81-81 1-Allyl lysergol 124-125 1-Allyluol203-205 Ergotamine (reference) 175-177 1-Allyl ergotamine 179-181Dihydroergotamine (reference) 237-238 1-Allyl dihydroergotamine 165-167Lisuride (reference) 173-175 1-Allyl lisuride 72-74 Terguride(reference) 206 1-Allyl terguride 66-67

B) MS data for 1-allyl terguride [m/z (relative intensity)]:

-   381 (10),380 (39), 308 (6), 307 (15), 265 (6), 264 (24), 263 (36),    249 (8), 221 (5), 220 (5), 209 (7), 208 (21), 207 (100), 195 (12),    194 (18), 100 (4), 74 (3).

C) NMR data for 1-allyl-(5R,8S,10R)-terguride:

¹³C NMR ¹H NMR Atom δ mult. δ ^(n)H mult.^(a) J(Hz)  2 121.73 d 6.774 1d 1.7  3 110.84 s  4 26.91 t 2.667 1 ddd 14.6, 11.1, 1.7 3.379 1 dd14.6, 4.3  5 67.61 d 2.205 1 ddd 11.1, 9.7, 4.3  7 61.89 t 2.485 1 dd11.7, 2.6 2.874 1 ddd 11.7, 2.6., 2.4  8 44.95 d 4.282 1 m  9 32.55 t1.636 1 ddd 13.2, 13.0, 3.3 2.796 1 dddd 13.2., 4.3, 2.6, 2.6 10 36.52 d3.052 1 m 11 133.52 s 12 112.83 d 6.888 1 ddd 6.9, 1.3, 0.9 13 122.73 d7.158 1 dd 8.3, 6.9 14 107.12 d 7.100 1 ddd 8.3, 0.9, 0.8 15 133.68 s 16126.71 s N—CH₃ 43.39 q 2.416 3 s N—C═O 156.57 s 1′ 48.91 t 4.674 2 ddd5.5, 1.7, 1.5 2′ 133.87 d 5.990 1 ddt 17.0, 10.2, 5.5 3′ 117.00 t 5.1241 ddt 17.0, 1.3, 1.7 5.188 1 ddt 10.2, 1.3, 1.5 α 41.06 t 3.250 1 dq14.5, 7.1 3.347 1 dq 14.5, 7.1 β 13.85 q 1.152 3 t 7.1 N—H 5.572 1 d 8.2

Example 2 Function Test Based on 5-HT_(2B) Receptor Tissue

The test was an in vitro function test to characterize 5-HT_(2B)receptors in a pig's pulmonary artery. The pig's pulmonary artery wasprepared as follows: Small branches were dissected from the pulmonaryartery and cautiously freed of organ tissue and connective tissue. Up tosix rings of the artery (length 2-3 mm and width 1.5-2 mm) were hung inhorizontal orientation between two L-shaped platinum hooks (150 μm indiameter) and fixed in an organ bath containing 10 ml of modifiedKrebs-Henseleit buffer composed as follows: 118 mM NaCl, 4.7 mM KCl, 2.5mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃, and 11 mMD-glucose. A continuous flow of a gas mixture of 95% O₂ and 5% CO₂passed through the solution which was kept at a constant temperature of350C. The preparations were connected to an isometric power converter(Hugo Sachs Elektronik, March, Germany), and voltage changes werecontinuously recorded. The constant voltage in stationary condition wasadjusted to 20 mN at the beginning of each experiment. During an initialstabilization period of 60 minutes, the bath medium was replaced every20 minutes and the voltage was repeatedly adjusted to 20 mN. The arterypreparations were stimulated at 45-minute intervals once with KCl (30mM) and three times with prostaglandin-F_(2α) (PGF_(2α), 3 μM) until theresponse by contraction was visible. The undamaged condition of theendothelium was evaluated functionally by measuring the extent ofendothelium-dependent relaxation following application of bradykinin (10nM). After the third PGF_(2α)-induced contraction had stabilized, therelaxation response was examined for 5-HT by determining a cumulativeconcentration-response curve in the absence and presence of theantagonist. FIG. 1 shows the effects on the relaxation response whenadding the 1-allyl ergotamine and 1-allyl dihydroergotamine, compoundsaccording to the invention.

The relaxation response to the test compound was examined using the samemethod as with 5-HT to test for agonistic activity. The concentration ofthe agonist was increased in increments at the time when the responsesignal had reached a plateau. The plateau was typically reached within 2to 4 minutes. The relaxation effects were expressed as a percentage ofthe PGF_(2α)-induced contraction. The antagonists were added 30 minutesbefore the recording of the agonist concentration response curvesstarted. The effects of the antagonists were examined in ring segmentsthat were adjacent to the reference segments.

Die antagonistic effect of the compounds according to the invention to5-HT_(2B) receptors was proved using this method (see Table 1).

The selective effect of 5-HT_(2A) receptors or 5-HT_(2B) receptors,respectively, was confirmed in a comparative screening.

Example 3 Function Test Based on 5-HT_(2A) Receptor Tissue

The example below describes an in-vitro function test for characterizing5-HT_(2A) receptors in rat's caudal arteries. The rat's caudal arterywas prepared using the method described by Schoning (Schoning et al.,2001, Die komplexe Wechselwirkung von Ergovalin mit 5-HT_(2A)-,5-HT_(1B/1D)-und alphai-Rezeptoren in isolierten Arterien von Ratten undGuinea-Schweinen, J. Anim. Sci., 79, pp. 2202-2209).

Male Wistar rats (250-300 g) were killed by suffocation. The anteriorcaudal artery was dissected fast and cleared of attached connectivetissue. A stainless steel wire (0.3 mm in diameter) was introduced intothe artery to strip off the endothelium. Up to 20 cylindrical segmentsof the artery (length 3-4 mm) were hung in horizontal orientationbetween two L-shaped platinum hooks (150 μm in diameter) and fixed in anorgan bath containing 20 ml of modified Krebs-Henseleit buffer composedas follows: 118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mMKH₂PO₄, 25 mM NaHCO₃, and 10 mM D-glucose. A continuous flow of a gasmixture of 95% O₂ and 5% CO₂ passed through the solution which was keptat a constant temperature of 37° C. The preparations were connected toan isometric power converter (W. Fleck, Mainz, Germany) coupled with aTSE 4711 conversion coupler and a Siemens C1016 compensograph forcontinuous recording of voltage modulation. The constant voltage wasadjusted to 5 mN at the beginning of each experiment. During anequilibrium period of 120 minutes, the preparations were stimulated onceafter 60 minutes with 5-HT (1 μM).

Three cumulative concentration-response curves (CRC) were determined foreach artery segment in these experiments for the study of partialagonists. The first CRC was obtained for 5-HT, the second that followed60 minutes later for the partial agonist. Finally, the third CRC wasobtained 10-15 minutes after the second CRC without washing with 5-HTand using the highest agonist concentration (0.3-3 μM). Additionalexperiments determined two CRCs at an interval of 60 minutes asdescribed above. The first CRC was determined for 5-HT. The second CRCwas determined to test the partial agonist in the presence ofketanserin. The preparations were incubated for 30 minutes with aketanserin solution (3 nM).

The axial shift to the right of the curves determined in the presence ofketanserin was compared to the shift determined for the respectivecontrol preparation in the absence of ketanserin. In these experimentsusing ketanserin, two separate CRCs to 5-HT were obtained from eachartery segment at a 90-minute interval. For the antagonists, thepreparations were incubated 60 minutes prior to determining the secondcurve. Prazosin (0.1 μM) and cocaine (6 μM) were present in the solutionduring these experiments to block the α₁-adrenoceptors and neuronalabsorption of 5-HT.

The test using the method described above proved that the compoundsaccording to the invention are partial or full antagonists of 5-HT_(2A)receptors (Table 1). TABLE 1 Test for antagonistic effects of 5-HT_(2A)and 5-HT_(2B) receptors Structure (acc. to formula I or II) 5-HT_(2A)5-HT_(2B) Bond Conc. pA₂ Conc. pA₂ Selectivity Compound R₁ R₂ R₃ R₄ R₅R₆ C⁹-C¹⁰ (nM) value (nM) value HT_(2A):HT_(2B) Lisuride —CH₃—NHCON(C₂H₅)₂ — H — — unsaturated 10 8.60 1 10.32  1:52 (reference)1-Allyl —CH₃ —NHCON(C₂H₅)₂ — H — — unsaturated 30 8.92 1000 8.17 6:1lisuride Terguride —CH₃ —NHCON(C₂H₅)₂ H H — — saturated 300 8.38 10 8.491:1 (reference) 1-Allyl —CH₃ —NHCON(C₂H₅)₂ H H — — saturated 30 8.701000 7.67 11:1  terguride Festu- —CH₃ H H —CH₃ — — saturated — 6.63 — —— clavine* (reference) 1-Allyl —CH₃ H H —CH₃ — — saturated 10-30 7.891000 6.74 14:1  festu- clavine Lysergol* —CH₃ H — —CH₂OH — — unsaturated— 6.88 — — — (reference) 1-Allyl- —CH₃ H — —CH₂OH — — unsaturated 3-100 8.45 1000 7.61 7:1 lysergol 1-Allyluol —CH₃ H —OCH₃ —CH₂OH — — saturated100 7.36 1000 7.03 2:1 1-Allyl di- —CH₃ H — Res. of —CH₃ Ben- saturated10 7.65 30 9.30  1:45 hydroergo- formula zyl tamine (II) 1-Allyl —CH₃ H— Res. of —CH₃ Ben- unsaturated 10 7.85 — 9.11**  1:18 ergotamineformula zyl (II)*Measured values from H. Pertz (1996) Planta Med. 62, pp. 387-392**−logKp, calculated according to Kenakin

1. Allyl ergot alkaloid derivatives of the general formula (I)

wherein R₁represents a methyl, ethyl, n-propyl, i-propyl,or allyl group,R₂is hydrogen or a NHCON(C₂H₅)₂ group, R₃is hydrogen or a —OCH₃ group,and R₄ represents a methyl, ethyl, n-propyl, i-propyl, or —CH₂OH group,a

group in which R₇ represents an unbranched or branched alkyl group, arylgroup, or aralkyl group containing 1-18 carbon atoms, a carboxy group ora group of the formula (II)

in which R₅ is an unbranched or branched alkyl group containing 1-4carbon atoms and R₆ is an unbranched or branched alkyl group containing1-5 carbon atoms, an aryl, an aralkyl or a —(CH₂)₂SCH₃ group, and thebond between C atoms 9 and 10 is either a single or a double bond whilethe residue R₃ is omitted.
 2. The allyl ergot alkaloid derivativesaccording to claim 1 wherein the residue R₁ is a methyl or ethylresidue.
 3. The allyl ergot alkaloid derivatives according to claim 1wherein the residue R₂ is a hydrogen atom.
 4. The allyl ergot alkaloidderivatives according to claim 1 wherein residue R₃ is a hydrogen atom.5. The allyl ergot alkaloid derivatives according to claim 1 whereinresidue R₄ is a hydrogen atom, a methyl group, or a residue of thegeneral formula (II)


6. The allyl ergot alkaloid derivatives according to claim 1 wherein theresidue R₅ is a methyl, ethyl, i-propyl, or s-butyl group.
 7. The allylergot alkaloid derivatives according to claim 1 wherein the residue R₆is a methyl, ethyl, i-propyl, s-butyl, i-pentyl, or benzyl residue. 8.Compounds of the general formula (I) according to claim 1, namely1-allyl terguride, 1-allyl festuclavine, and 1-allyl dihydroergotamine.9. A method for producing the compounds of the general formula (I)according to claim 1 wherein a compound of the general formula (III)

wherein R₁ represents a methyl, ethyl, n-propyl, i-propyl, or allylgroup, R₂ is hydrogen or a NHCON (C₂H₅)₂ group, R₃ is hydrogen or a—OCH₃group, and R4 represents a methyl, ethyl, n-propyl, i-propyl, or—CH₂OH group, a

group in which R₇ represents an unbranched or branched alkyl group, arylgroup, or aralkyl group containing 1-18 carbon atoms, a carboxy group ora group of the formula (II)

in which R₅ is an unbranched or branched alkyl group containing 1-4carbon atoms and R₆ is an unbranched or branched alkyl group containing1-5 carbon atoms, an aryl, an aralkyl or a —(CH₂)₂SCH₃group, and thebond between C atoms 9 and 10 is either a single or a double bond whilethe residue R₃ is omitted, is reacted with allyl bromide in CH₂Cl₂,optionally adding tetraethyl ammonium hydroxide and NaOH.
 10. Apharmaceutical composition containing at least one compound of thegeneral formula (I) according to claim 1 as well as one or severalpharmacologically safe adjuvants and/or substrates.
 11. Use of thecompounds of the general formula (I) according to claim 1 and theirpharmaceutically tolerable salts as pharmaceuticals for the preventionand/or treatment of migraine.
 12. Use of the compounds of the generalformula (I) according to claim 1 and their pharmaceutically tolerablesalts as pharmaceuticals for the treatment of Parkinson's disease. 13.Use of the compounds of the general formula (I) according to claim 1 andtheir pharmaceutically tolerable salts for the prevention and/ortreatment of thrombocyte aggregation.
 14. Use of the compounds of thegeneral formula (I) according to claim 1 and their pharmaceuticallytolerable salts for the prevention and/or treatment of mental diseases.15. Use of the compounds of the general formula (I) according to claim 1and their pharmaceutically tolerable salts as pharmaceuticals for thetreatment of diseases of the nervous system.